tbuckley/cabot-search huggingface dataset:
Abstract 6133: Intratumoral budding in pretreatment biopsies can predict prognosis and neoadjuvant therapy response among the tumor microenvironmental components in colorectal adenocarcinoma
Authors: Kwangil Yim, Won Mo Jang, Yosep Chong, OK Ran Shin, Kyung Jin Seo
Journal: Cancer Research (2022)

Abstract Purpose: Neoadjuvant therapy has been used as one of a treatment option in locally advanced rectal cancer and unresectable colorectal cancers (CRCC) with oligo-metastasis. Considering that radical specimen has been deformed due to this treatment, predicting prognosis is more complex. We evaluated several tumor microenvironmental factors in the pretreatment biopsies; those were known as prognostic factors in radical specimen. Methods: From 2010 to 2021, 85 patients with neoadjuvant therapy and surgery for CRCC were enrolled in Uijeongbu St. Mary’s hospital. Intratumoral budding (ITB), tumor stromal ratio, presence of immature stroma and Klintruo-Makinen grade for inflammatory cells were evaluated in pretreatment biopsies by three pathologists, independently. Results: Only high grade ITB (OS: p = 0.030, CSS: p = 0.005, DFS: p &amp;lt; 0.001) was poor survival factor in univariate analysis. In addition, high grade ITB was related with pathological stage (p = 0.017), lymphatic invasion (p = 0.010) and chemoresistance in non-metastatic CRCC group (p = 0.046). Presence of immature fibrosis was related with clinical stage (p = 0.045) and pathological stage (p = 0.033). In multivariate analysis, high grade ITB was independent poor survival factor (OS: p = 0.031, CSS: p = 0.009, DFS: p = 0.001). Conclusion: Our study revealed that high grade ITB in pretreatment biopsied was poor survival factor in CRCC with neoadjuvant treatment. In our observation, we recommend that ITB result should be included in the pathology report when considering neoadjuvant treatment. Citation Format: Kwangil Yim, Won Mo Jang, Yosep Chong, OK Ran Shin, Kyung Jin Seo. Intratumoral budding in pretreatment biopsies can predict prognosis and neoadjuvant therapy response among the tumor microenvironmental components in colorectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6133.
Abstract 3207: Notch decoys as potential anti-angiogenic biotherapeutics
Authors: Timothy Sargis, Seock-Won Youn, Hyun Lee, L.A. Naiche, Jan Kitajewski
Journal: Cancer Research (2022)

Abstract Notch signaling is activated by ligands Delta-like 4 (Dll4) and Jagged1 in the tumor microenvironment to promote tumor angiogenesis and perfusion. Notch activation is associated with poor outcomes in several cancers, particularly triple negative breast cancer (TNBC), and affects both tumor angiogenesis and metastasis. The development of therapeutics targeting angiogenesis, such as the Notch pathway, has again attracted attention. Previous approaches to globally inhibit the Notch pathway or block Dll4/Notch1 activation, such as γ-secretase inhibitors (GSI), have raised safety concerns due to gastrointestinal toxicity due to accumulation of secretory goblet cells in the intestine. Similarly, anti-Dll4 therapy resulted in pathological changes in the liver as well as severe vascular neoplasms when evaluated using preclinical animal models. Development of new approaches for targeting the Notch pathway remains a critical clinical problem currently unaddressed. Our lab has previously developed ligand-specific inhibitors of Notch signaling, called Notch decoys, which are comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain. These Notch decoys bind ligand non-productively and interfere with ligand function. Jagged-specific Notch1 decoys inhibit angiogenesis in vitro and significantly impair tumor growth, tumor angiogenesis, and perfusion without apparent toxicity in mouse models of TNBC. However, this previous work utilized Notch decoys produced via viral expression vectors, which preclude dosage control and limit clinical applicability. We have developed a new generation of Notch “mini” decoys that contain fewer EGF-like repeats. These mini decoys show improved secretion characteristics and can be purified as active proteins in clinically relevant quantities. Using a variety of binding assays, we observed that these Notch mini decoys demonstrate strong but distinct binding to Notch ligands Dll4 and Jagged1 and block Notch signaling when evaluated in cultured cells. Our newly generated Notch decoys can now be sufficiently purified for use in a dose-dependent manner to test the therapeutic role of Notch inhibition on tumor angiogenesis using preclinical animal models. Citation Format: Timothy Sargis, Seock-Won Youn, Hyun Lee, L.A. Naiche, Jan Kitajewski. Notch decoys as potential anti-angiogenic biotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3207.
Abstract 6315: Are a subset of patients at higher risk for mortality in stage III colon cancer: An analysis of the SEER database
Authors: Luv N. Hajirawala, Yong Yi, Michelle A. Bergeron, Danielle A. Dooley, Guy R. Orangio, Elyse R. Bevier-Rawls, Kurt G. Davis, Jeffrey S. Barton
Journal: Cancer Research (2022)

Abstract Background: High-risk features (HRF) increase mortality for Stage II colon cancer (CC). These HRF include pathologic T4 disease, perineural invasion (PNI), lymphovascular invasion (LVI), an inadequate lymphadenectomy (less than 12 lymph nodes harvested) and poorly differentiated tumors. The presence of two or more HRF has an additive impact on survival for patients with Stage II CC. While T4 and disease greater than N1a raise the risk of mortality in Stage III CC, the effect of the other accepted HRF in patients with Stage III CC has not been studied. Materials and Methods: Surveillance, Epidemiology and End Results (SEER) (2010 - 2017) was used to identify patients with Stage III and IV CC. Patients with Stage III CC were then further classified by the presence of zero, 1, or 2 or more of the following HRF: pathologic T4, PNI, inadequate lymphadenectomy, or poor differentiation. Overall (OS) and cause-specific (CS) survival were calculated. Results: 57,640 patients with Stage III or IV CC were identified. 35,760 (62%) patients had Stage III disease and 21,880 (38%) had Stage IV disease. Among patients with Stage III disease, 16,733 (46.8%) had no HRF, 12,703 (35.5%) had 1 HRF and 6,324 (17.7%) had 2 or more HRF. For patients with 1 HRF, 4,610 (36.3%) had poor differentiation, 2,339 (18.4%) had PNI, 3,673 (28.9%) had T4 disease, and 2,078 (16.4%) had an inadequate nodal harvest. Patients with Stage III CC without HRF had the best OS (73.3%) and CS (81.4%,). This was followed by Stage III with 1 HRF (OS 63.7%, CS 71.6%) and Stage III with 2 or more HRF (OS 44%, CS 51%). Patients with Stage IV disease had the worst OS (18.1%) and CS (20.4%) (p&amp;lt;0.05). For patients with 1 HRF, pathologic T4 conferred worse OS (57.2%) and CS (63.2%), compared to PNI (OS 66.4%, CS 73.7%), inadequate lymphadenectomy (OS 64.6%, CS 74.9%) and poor differentiation (OS 66.6%, CS 75.4%) (p&amp;lt;0.01). Conclusion: HRF have a cumulative influence on OS and CS in patients with Stage III CC. The presence of multiple HRF should be considered higher risk for patients with Stage III disease. Citation Format: Luv N. Hajirawala, Yong Yi, Michelle A. Bergeron, Danielle A. Dooley, Guy R. Orangio, Elyse R. Bevier-Rawls, Kurt G. Davis, Jeffrey S. Barton. Are a subset of patients at higher risk for mortality in stage III colon cancer: An analysis of the SEER database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6315.
Racism is forcing ethnic minority doctors to leave jobs, warns BMA report
Authors: Gareth Iacobucci
Journal: BMJ (2022)

Widespread racism in the medical workforce is “wrecking the lives of many doctors” and forcing some to quit the profession, a hard hitting report from the BMA has warned. The report, Racism In Medicine ,1 surveyed 2030 UK doctors and medical students on their experience of racism in the medical profession and the workplace. The survey results and testimonies (box 1) led the BMA to conclude that widespread racism exists on a personal and institutional level, stemming from doctors, other NHS staff, and patients. Box 1 ### Examples of comments reported by survey respondentsRETURN TO TEXT
Abstract 5552: Novel set of OX40 targeted antibodies and VHHs include agonists and antagonists for future development
Authors: Chenguang Cai, Xiang Li, Shin-Chen Hou, Guoqian Sun, Ying Li, Ting Yang, Fengzhi Zhang, Qi Sun, Shiying Fu, Shuang Zhao, You'you Lin, Feizheng Xue
Journal: Cancer Research (2022)

Abstract Immunotherapy is one of the most effective modern treatments for cancer. While immunotherapy operates through a broad class of mechanisms, modulating immune checkpoints have provided some of the most effective approaches, including inhibition of PD-1/PD-L1 pathway, CTLA-4, LAG-3, OX40, Tim-3, KIR and TIGIT to reverse tumor immune escape.OX40, also known as CD134 or TNFRSF4, is a membrane protein expressed in CD4+ and CD8+ T cells, neutrophils and NK cells. In the process of T cell activation, OX40 plays a synergistic stimulating function by binding with ligand OX40L. OX40 agonist immunotherapy has been previously shown to improve the survival rate of glioblastoma in mice, prevent tumor growth in ovarian cancer, increase the prognostic significance of CD8+ cell infiltration in colorectal cancer, and eliminate the inhibitory function of Foxp3+ Treg cells that constitutively Express OX40. On the contrary, blocking OX40 axis is a promising strategy to treat T cell hyperactivation in autoimmune diseases. As recently reported in the literature, a two-armed, random, double blinded phase 2b clinical trial demonstrated that telazorlimab, an antagonist OX40 antibody developed by Ichnos Sciences, met primary efficacy endpoints in treating atopic dermatitis.In this research, we developed a set of novel antibodies to OX40 using a hybridoma and VHH synthetic library; the set of antibodies includes both agonists and antagonists.We developed one hybridoma origin mAb into a human framework. Agonist activity was equal to MOXR0916 in NF- κB reporter-Jurkat assay, dependent on coupling by proteinA/cell-bound CD32b, non-competing with OX40L, and epitope mapped to domain 2+3.We identified dozens of binders from our synthetic single domain VH library. After construction into a IgG1Fc fusion form, 4 VHHs were obtained with significant agonistic activity, dependent on coupling by proteinA/cell bound CD32b. Another 5 VHHs were also obtained with significant antagonistic activity without coupling by proteinA/cell-bound CD32b. The 4 agonistic VHHs were confirmed with binding to domain 1+2, competitive to OX40L’s binding.These VHHs constructs represent a promising set of novel biologics to modulate OX40—as agonists or antagonists—and serve as the basis for development of potential new therapies in the clinic. Citation Format: Chenguang Cai, Xiang Li, Shin-Chen Hou, Guoqian Sun, Ying Li, Ting Yang, Fengzhi Zhang, Qi Sun, Shiying Fu, Shuang Zhao, You'you Lin, Feizheng Xue. Novel set of OX40 targeted antibodies and VHHs include agonists and antagonists for future development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5552.
Abstract 1218: HOPE2Net: Integrating histological features and position embeddings in spatially resolved transcriptomics to predict gene expression and pathway activities from histology images in tumors
Authors: Kenong Su, Minxing Pang, Mingyao Li
Journal: Cancer Research (2022)

Abstract Recent developments in spatially resolved transcriptomics (SRT) technologies have enabled the profiling of transcriptome-wide gene expression while retaining spatial location information of each measured spot within a tissue. Meanwhile, the corresponding histopathology images of tissue sections are readily available and can be aligned to the measured spots. Given that the histology images are practically more convenient and affordable to obtain, we designed HOPE2Net, a multi-layer perceptron architecture, that leverages information provided by SRT data to predict gene expression and pathway activities from histology images. Through systematic evaluations of different approaches for extracting deep image features and cellular morphology features, HOPE2Net performs feature selections from a pre-trained Vision Transformer, which is the state-of-art deep learning model for image recognition. After extracting histological image features, HOPE2Net further integrates with position embeddings, to optimize the gene expression and pathway activity prediction tasks. Through analyzing breast cancer and prostate cancer SRT datasets obtained from numerous tissue sections in multiple patients, we demonstrate that HOPE2Net can accurately predict the gene expression patterns for highly variable genes and the activities for significantly enriched domain-specific pathways. We further show that the predicted gene expression and pathway activities can help detect cancer subtypes and aid in treatment decision-makings. Given the growing interest in applying SRT in cancer genomics, we believe HOPE2Net holds the potential in identifying biomarkers from direct screenings of tissue histology images, which may be implemented in clinical studies for cancer diagnoses and decision-making processes. Citation Format: Kenong Su, Minxing Pang, Mingyao Li. HOPE2Net: Integrating histological features and position embeddings in spatially resolved transcriptomics to predict gene expression and pathway activities from histology images in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1218.
Abstract 3298: Propagation competence of a self-antigen-targeting arenavirus vector based cancer therapy determines antitumor efficacy in mouse melanoma
Authors: Mette-Triin Purde, Fabienne Hartmann, Jovana Cupovic, Sarah Schmidt, David Bomze, Felix Stemeseder, Alexander Lercher, Lenka Besse, Fiamma Berner, Thomas Tüting, Andreas Bergthaler, Andrea Schietinger, Stefan Kochanek, Burkhard Ludewig, Klaus K. Orlinger, Tobias Bald, Sandra S. Ring, Lukas Flatz
Journal: Cancer Research (2022)

Abstract Breaking self-tolerance and inducing a robust immune response targeting tumor cell derived self-antigens by therapeutic vaccines has remained challenging. We have generated a replicating viral vector based on the arenavirus lymphocytic choriomeningitis virus expressing the melanoma tissue-specific self-antigen Trp2 (artLCMV-Trp2) and show that a single immunization of mice bearing established melanoma with this vector can break tolerance against this self antigen and induces high levels of tumor-infiltrating TRP2+ CD8+ T cells. These T cells express the effector cytokines IFNγ and TNFα, lack markers of T cell exhaustion, and their appearance coincides with marked inhibition of tumor growth and significant survival benefit. artLCMV-TRP2 induced a strong type I interferon response that resulted in transient type I-dependent Treg inhibition that was necessary for the generation of optimal antitumoral T cell responses. Moreover, artLCMV-TRP2 vaccination proved able to induce complete tumor remission when combined with infusion of exogenous TRP2-specific T cells into mice. In conclusion, replication competence is a key property of artLCMV-TRP2 that enabled effective anti-cancer immunity and therapeutic effect. Citation Format: Mette-Triin Purde, Fabienne Hartmann, Jovana Cupovic, Sarah Schmidt, David Bomze, Felix Stemeseder, Alexander Lercher, Lenka Besse, Fiamma Berner, Thomas Tüting, Andreas Bergthaler, Andrea Schietinger, Stefan Kochanek, Burkhard Ludewig, Klaus K. Orlinger, Tobias Bald, Sandra S. Ring, Lukas Flatz. Propagation competence of a self-antigen-targeting arenavirus vector based cancer therapy determines antitumor efficacy in mouse melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3298.
Flow-mediated dilation reference values for evaluation of endothelial function and cardiovascular health
Authors: Christian Heiss, Ana Rodriguez-Mateos, Mariam Bapir, Simon S Skene, Helmut Sies, Malte Kelm
Journal: Cardiovascular Research (2022)

Abstract Aims Endothelial function is essential for cardiovascular health, and flow-mediated dilation (FMD) is an established technique to measure it. This paper aims to assess FMD values in apparently healthy individuals and provides reference values to facilitate wider clinical use. Methods and results In 1,579 apparently healthy individuals (aged 18–76), fasted FMD values (data from 44 studies, 6 institutions, 22 operators) were normally distributed and inversely univariately correlated with age, body mass index, glucose, cholesterol, blood pressure, and brachial artery (BA) diameter. Significant multivariate predictors of FMD were age (−0.4%/decade), BMI (0.04%/kg/m2), smoking (−0.7%), and BA diameter (−0.44%/mm) that together explained 19% of the variability independent of operator, institution or ultrasound machine. Individuals in the high FMD tertile (&amp;gt;6.8%) were younger, had smaller BA diameter, lower blood pressure and cholesterol. In individuals with low- and intermediate fatal cardiovascular risk (SCORE), 26% and 53% of individuals, respectively, had FMD values in the low tertile (&amp;lt;5.4%). After adding data from 385 patients with stable coronary artery disease (CAD), ROC analysis (c = 0.841, P &amp;lt; 0.001) showed that FMD of &amp;gt;6.5% excluded CAD (95% sensitivity; 60% specificity) and FMD &amp;lt;3.1% excluded 95% healthy individuals (95% specificity, 31% sensitivity). A meta-analysis and meta-regression of 82 clinical trials (11 countries, n = 3,509) using similar FMD methodology showed that despite considerable heterogeneity (I2 = 0.97) FMD in healthy individuals was on average 6.4% (95%CI: 6.2%, 6.7%) with no significant differences between countries but a significant age-dependent decline (−0.3%/decade, R2 = 0.13). Conclusions We provide an age-adapted frame of FMD reference intervals in apparently healthy individuals for use as a biomarker of cardiovascular health. As the degree of vascular endothelial function integrates environmental and genetic factors with classical CV risk factors, FMD may more comprehensively classify individuals with and without standard modifiable cardiovascular risk factors and serve as a target for cardiovascular prevention.
Abstract 2555: Immunophenotyping early stage lung adenocarcinomas (LUAD) by histologic subtype
Authors: Zhanhao Xi, Roxana Pfefferkorn, Eric Burks, Jennifer Beane, Sarah Mazzilli
Journal: Cancer Research (2022)

Abstract The immune microenvironment is thought to influence Lung Adenocarcinoma (LUAD) subtype formation, disease progression, and thus patient outcome. Despite recent advancements in screening, immunotherapy, and targeted therapy, the biology of aggressive LUAD is still poorly understood, and in-depth characterization associated with LUAD histologic subtypes and progression are needed. In this study, we sought to measure the immune environment associated with different LUAD subtypes using Imaging Mass Cytometry (IMC). IMC has emerged as a powerful new tool that enables the multiplex imaging of more than 50 markers simultaneously, quantify multiple protein expressions at a single cell level, and preserve tissue spatial information. We stained a tissue microarray of early stage LUAD patient samples, representing different LUAD subtypes, with a panel of 21 antibodies. These antibodies are designed to phenotype immune cell subsets, as well as using Ki67 to stain for highly proliferative epithelial cells. This will allow us to better understand how different immune cells are interacting with each other, as well as how they interact with highly proliferating epithelial cells. The resulting ablated samples generate images containing antibody intensity and coordinates, which we then perform cell segmentation to generate single cell data. The marker expression is then quantified, and single cell data analyzed using HistoCAT. Cell neighborhood interactions are analyzed based on spatial relationships, and similarly interacting cells are grouped into phenoclusters. Our results suggest that a Ki67 high phenocluster within solid LUAD subtypes have fewer macrophages (CD68, CD163) and T cell populations (CD8, CD4, FOXP3), however, are enriched for plasma B cells (CD20) and immune suppressive populations (PD1, PDL1). In contrast, a Ki67 high cluster within lepidic subtypes are enriched for of macrophage (CD68) and T cell populations (CD8, CD4, FOXP3). Using IMC, we have begun to identify immune subset shifts in LUAD. This early analysis of LUAD using IMC begins to shed light on the immune regulation that may indicate progression and/or guide intervention approaches. Citation Format: Zhanhao Xi, Roxana Pfefferkorn, Eric Burks, Jennifer Beane, Sarah Mazzilli. Immunophenotyping early stage lung adenocarcinomas (LUAD) by histologic subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2555.